Antibodies to IL-15 and uses thereof

Abstract

The present invention relates to antibodies binding IL-15, in particular humanized antibodies. In particular, the anti-IL-15 antibodies according to the invention are able to neutralize IL-15 activity and are useful in the prevention and/or treatment of an autoimmune disease and/or inflammatory disorder, a malignancy, transplant rejection, metabolic condition and/or an infectious disease caused by parasitic, viral or bacterial pathogens.

The invention claimed is: 
     
       1. A method of treating an IL-15 related disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment or a pharmaceutical composition thereof, said antibody or antigen-binding fragment comprising:
 (1) a heavy chain variable region comprising SEQ ID NO: 5 or any variant thereof wherein 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acids of said sequence are substituted by a different amino acid, and 
 2) a light chain variable region comprising SEQ ID NO: 24 or any variant thereof wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids of said sequence are substituted by a different amino acid, 
 wherein said treatment causes regression of said IL-15 related disease or disorder and/or its symptoms. 
 
     
     
       2. The method according to  claim 1 , wherein the IL-15 related disease or disorder is selected from an autoimmune disease, an inflammatory disorder, a malignancy, a metabolic disease, an infectious disease caused by parasitic, viral or bacterial pathogens, a hypermetabolic condition, amyloid related disorders and/or a transplant rejection, wherein:
 said autoimmune disease and inflammatory disorder is rheumatoid arthritis, psoriasis, celiac disease, refractory celiac disease, sarcoidosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, hepatitis C-induced liver disease, multiple sclerosis, auto-immune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, biliary atresia, alopecia areata, transplant rejection response, or eosinophilic esophagitis; 
 wherein said malignancy is T-cell leukemia, cutaneous T-cell lymphoma (CTCL), mycosis fungoides, Sezary syndrome, lymphoproliferative disorder of granular lymphocytes (LDGL), large granular lymphocytic leukemia, acute lymphocytic leukemia (ALL), pre-B cell leukemia, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, melanoma, small cell lung cancer, renal cell carcinoma, glioblastoma, neuroblastoma, or mesothelioma; 
 wherein said infectious disease caused by parasitic, viral or bacterial pathogens is selected from granulomatous infections, tuberculosis, leishmaniasis, schistosomiasis, cytomegalovirus infections, hantaviruses infections, hantavirus haemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome; 
 wherein said metabolic disease is diabetes or muscular dystrophy; and 
 said hypermetabolic condition is sickle cell disease, trauma, infection or cancer-associated cachexia. 
 
     
     
       3. The method according to  claim 2 , wherein the IL-15 related disease or disorder is an autoimmune disease or inflammatory disorder. 
     
     
       4. The method according to  claim 3 , wherein the IL-15 related disease or disorder is eosinophilic esophagitis. 
     
     
       5. The method according to  claim 1 , wherein the IL-15 related disease or disorder is rheumatoid arthritis, psoriasis, celiac disease, refractory celiac disease, sarcoidosis, inflammatory bowel disease, hepatitis C-induced liver disease, multiple sclerosis, auto-immune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, biliary atresia, alopecia areata, transplant rejection, Alzheimer's disease, viral infection, Hantaan viral infection, or eosinophilic esophagitis. 
     
     
       6. The method according to  claim 1 , wherein the IL-15 related disease or disorder is celiac disease. 
     
     
       7. The method according to  claim 1 , wherein the IL-15 related disease or disorder is alopecia areata. 
     
     
       8. The method according to  claim 1 , wherein said antibody or antigen-binding fragment thereof is to be administered in combination with a co-agent for treatment of an autoimmune disease and/or inflammatory disorder, a malignancy, transplant rejection, metabolic disease and/or an infectious disease caused by parasitic, viral or bacterial pathogens, or a compound lowering intestinal inflammation, and/or protecting intestinal mucosa, and/or lowering the immune reactivity of gluten peptides, and/or modifying the gut microbiota. 
     
     
       9. The method according to  claim 1 , wherein the antibody or antigen-binding fragment thereof, comprises:
 (1) a heavy chain variable region comprising SEQ ID NO: 5 or any variant thereof having at least 95% identity with SEQ ID NO: 5, and 
 (2) a light chain variable region comprising SEQ ID NO: 24 or any variant thereof having at least 95% identity with SEQ ID NO: 24, 
 or an antigen-binding fragment thereof. 
 
     
     
       10. The method according to  claim 1 , wherein the antibody is a humanized antibody. 
     
     
       11. The method according to  claim 1 , wherein the antibody or antigen-binding fragment comprises:
 (1) a heavy chain variable region comprising SEQ ID NO: 5 or any variant thereof wherein 1, 2, 3, 4, 5 or 6 amino acids selected among:
 (i) arginine (R) at position H3 (VH RH3), methionine (M) at position H5 (VH MH5), alanine (A) at position H6 (VH AH6), alanine (A) at position H49 (VH AH49), 
 (ii) aspartic acid (D) at position H61 (VH DH61), serine (S) at position H62 (VH SH62), 
 (iii) methionine (M) at position H98 (VH MH98), tryptophan (W) at position H100C (VH WH100C), and methionine (M) at position H100E (VH MH100E), 
 
 are substituted by a different amino acid, and 
 (2) a light chain variable region comprising SEQ ID NO: 24 or any variant thereof wherein 1, 2, 3, or 4 amino acids selected among:
 (i) tyrosine (Y) at position L36 (VL YL36), leucine (L) at position L46 (VL LL46), 
 (ii) aspartic acid (D) at position L91 (VL DL91), and serine (S) at position L92 (VL SL92), 
 
 are substituted by a different amino acid. 
 
     
     
       12. The method according to  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises:
 (1) a variant of SEQ ID NO: 5 that comprises the amino acid sequence of SEQ ID NO: 5 except that:
 (i) VH RH3 is substituted by glutamine (Q), and/or VH MH5 is substituted by valine (V), and/or VH AH6 is substituted by glutamic acid (E), and/or VH AH49 is substituted by serine (S), and/or 
 (ii) VH DH61 is substituted by glutamic acid (E), and/or VH SH62 is substituted by threonine (T), and/or 
 (iii) VH MH98 is substituted by leucine (L), phenylalanine (F), isoleucine (I), or alanine (A), and/or VH WH100C is substituted by tyrosine (Y), phenylalanine (F), or alanine (A), and/or VH MH100E is substituted by leucine (L), phenylalanine (F), or isoleucine (I), and/or 
 
 (2) a variant of SEQ ID NO: 24 that comprises the amino acid sequence of SEQ ID NO: 24 except that:
 (i) VL YL36 is substituted by phenylalanine (F), and/or VL LL46 is substituted by arginine (R), and/or 
 (ii) VL DL91 is substituted by glutamic acid (E), and/or VL SL92 is substituted by threonine (T). 
 
 
     
     
       13. The method according to  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises:
 (1) a heavy chain variable region comprising SEQ ID NO: 5 except that:
 (i) VH RH3 is substituted by glutamine (Q), and/or VH MH5 is substituted by valine (V), and/or VH AH6 is substituted by glutamic acid (E), and/or 
 (ii) VH SH62 is substituted by threonine (T), and/or 
 (iii) VH WH100C is substituted by tyrosine (Y), and 
 
 (2) a light chain variable region comprising SEQ ID NO: 24. 
 
     
     
       14. The method according to  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises:
 (1) a heavy chain variable region selected from: SEQ ID NO: 6, SEQ ID NO: 12, SEQ ID NO: 21, and SEQ ID NO: 5, and 
 (2) a light chain variable region comprising SEQ ID NO: 24. 
 
     
     
       15. The method according to  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising SEQ ID NO: 6 and a light chain variable region comprising SEQ ID NO: 24. 
     
     
       16. The method according to  claim 1 , wherein the IL-15 related disease or disorder is Alzheimer's disease, Parkinson's disease or Huntington's disease.